Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2014 Feb;22(2):257-264.
doi: 10.1038/mt.2013.264. Epub 2013 Nov 13.

Genetically modified hematopoietic stem cell transplantation for HIV-1-infected patients: can we achieve a cure?

Patrick Younan  1 , John Kowalski  1 , Hans-Peter Kiem  2
Affiliations
Review

Genetically modified hematopoietic stem cell transplantation for HIV-1-infected patients: can we achieve a cure?

Patrick Younan et al. Mol Ther. 2014 Feb.

Abstract

The cure of a human immunodeficiency virus (HIV)-1-infected patient following allogeneic transplantation from a CCR5-null donor and potential cure of two patients transplanted with CCR5 wild-type hematopoietic stem cells (HSC) have provided renewed optimism that a potential alternative to conventional antiretroviral therapy (ART) is forthcoming. While allogeneic grafts have thus far suggested complete eradication of viral reservoirs, it has yet to be observed following autologous HSC transplantation. Development of curative autologous transplantation strategies would significantly increase the number of treatable patients, eliminating the need for matched donors and reducing the risks of adverse events. Recent studies suggest gene therapy may provide a mechanism for developing curative therapies. Expression of cellular/artificial restriction factors or disruption of CCR5 has been shown to limit viral replication and provide protection of genetically modified cells. However, significant obstacles remain with regards to the depletion of established viral reservoirs in an autologous transplantation setting devoid of the "allo-effect". Here, we discuss results from early-stage clinical trials and recent findings in animal models of gene modified HSC transplantation. Finally, we propose innovative combination therapies that may aid in the reduction and/or elimination of viral reservoirs in HIV-1-infected patients and promote the artificial development of a natural controller phenotype.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Achieving immunological control in human immunodeficiency virus (HIV)-1–infected patients. (a) Genetic modification of target cells (hematopoietic stem cells or CD4+ T cells) has been shown to significantly reduce viral infectivity in vitro and in vivo. Disruption of CCR5 prevents infection from R5-tropic strains while expression of the mC46-fusion inhibitor prevents infection of HIV regardless of viral tropism. (b) The development of infection-resistant immune cell populations following infusion of genetically modified hematopoietic stem cells (HSCs) or CD4+ T cells promotes an enhanced immune response against HIV (e.g., antibody response) and HIV-infected cells (e.g., cytotoxic T-cell response). Protected cells maintain functional activity improving both innate and adaptive immune responses against the virus, in addition to reducing the number of potential target cells, which serve to further reduce the latent reservoir. (c) Elimination of viral reservoirs will require the identification of latently infected cells in order to promote targeted deletion of infected cells through immunological responses or through targeted therapies. Reagents including Prostratin or suberoylanilide hydroxamic acid have previously been shown to promote viral reactivation in latently infected cells. Following the induced expression and transport of viral antigens to the plasma membrane of infected cells, targeted therapies such as aptamer-mediated delivery of toxic siRNAs can be utilized to diminish and/or eliminate viral reservoirs. (d) Highly conserved sequences within the viral genome can be targeted with sequence specific nucleases to disrupt or delete conserved regions fundamentally required for viral replication (e.g., transactivation response element).
Figure 2
Figure 2
Postinfusion vaccination and priming of immune response prior to cessation of highly active antiretroviral therapy (HAART). (a) Infected patients receiving HAART maintain nonmodified, human immunodeficiency virus (HIV)-specific CD4+ T cells; however, following infusion and engraftment of hematopoietic stem cells (HSCs), genetically modified, infection-resistant CD4+ T-cells specific for SHIV-antigens have yet to be exposed to viral antigens. (b) Following conventional vaccination, both nonmodified and genetically modified, HIV-specific CD4+ T-cell responders are expanded and primed for exposure to replicating virus upon cessation of HAART. (c) Following end of HAART treatment, latently infected cells express viral antigens and release nascent virions. Nonmodified CD4+ T-cells are targets for infection and will undergo apoptosis due to direct viral cytopathic effects or due to immunological recognition. Gene modified CD4+ T-cells that are resistant to infection, will detect viral antigens as peptide-MHCII complexes and elicit an immune response. By pre-exposing genetically modified cells to viral antigens via post-engraftment vaccination (and while on ART), SHIV-specific, infection-resistant CD4+ T cells can be generated prior to cessation of ART, which in turn, will activate and maintain a functional immune response upon activation of latent reservoirs. IR, immune response.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Hutter G, Nowak D, Mossner M, Ganepola S, Mussig A, Allers K, et al. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. N Engl J Med. 2009;360:692–698. - PubMed
    1. Douek DC, Brenchley JM, Betts MR, Ambrozak DR, Hill BJ, Okamoto Y, et al. HIV preferentially infects HIV-specific CD4+ T cells. Nature. 2002;417:95–98. - PubMed
    1. Heeney JL. The critical role of CD4(+) T-cell help in immunity to HIV. Vaccine. 2002;20:1961–1963. - PubMed
    1. Yukl SA, Boritz E, Busch M, Bentsen C, Chun TW, Douek D, et al. Challenges in detecting HIV persistence during potentially curative interventions: a study of the Berlin patient. PLoS Pathog. 2013;9:e1003347. - PMC - PubMed
    1. Henrich TJ, Hu Z, Li JZ, Sciaranghella G, Busch MP, Keating SM, et al. Long-term reduction in peripheral blood HIV type 1 reservoirs following reduced-intensity conditioning allogeneic stem cell transplantation. J Infect Dis. 2013;207:1694–1702. - PMC - PubMed

Publication types